All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Lipids in general are the building blocks of life. They are used as building blocks of membranes, cells and tissues, as energy sources, either immediate or stored, as precursors to a variety of other bio-molecules, as well as biochemical signals. In all biochemical processes lipids have an important role.
Many lipids, and especially triglycerides, are consumed in the human nutrition on a daily basis. In most cases, these lipids are metabolized and used for energy storage, as precursors for the biosynthesis of other lipids or bio-molecules. Whatever the fate of the lipids in the metabolic pathways, during and after their consumption, they interact with other nutrients or their metabolic products.
Fatty acids in human milk fat have a highly specific positional distribution on the glycerol backbone. This specific configuration is known to have a major contribution to the efficiency of nutrient absorption.
Palmitic acid (C16:0) is the predominant saturated fatty acid in mature human milk, constituting 20-25% of the fatty acids. 70-75% of this fatty acid is esterified at the sn-2 position of the triglycerides. In contrast, palmitic acid present in vegetable oils, which are most commonly used in the manufacture of infant formulas, is esterified at the sn-1 and sn-3 positions, while the sn-2 position is predominantly occupied by unsaturated fatty acids. The reason for the preferential esterification of palmitic acid to the sn-2 position of glycerol during the synthesis of triglycerides in the mammary gland in uncertain.
Several studies have demonstrated the preferential absorption of palmitic acid when present at the triglyceride sn-2 position [Lien E L. et al. (1997) J. Ped. Gastr. Nutr.; 52(2):167-174; Carnielli V P. et al. (1995) Am. J. Clin. Nutr.; 61:1037-1042; Innis S M. et al. (1993) Am. J. Clin. Nutr.; 57:382-390; Filer L. J. et al. (1969) J. Nutr.; 99:293-8]. The greater absorption of fat and calcium in breast-fed infants compared with those fed formula has been ascribed to two factors: the presence in breast milk of a lipolytic enzyme (the bile salt-stimulated lipase) and the relatively high proportion of palmitic acid at the sn-2 position of the triglyceride [Hernell O. et al. (1988) Perinatal Nutrition. New York: Academic Press.; 259-272; Wang C S. et al. (1983) J. Biol. Chem.; 258:9197-9202]. Higher palmitic acid absorption was obtained with formulas rich in palmitic acid esterified in the sn-2 position of the triglycerides, than with those containing palmitic acid predominantly esterified in the sn-1,3 position [López-López A. et al. (2001) Early Hum. Dev.; 65:S83-S94].
Calcium Absorption
During the first year of life, an infant's birth weight triples and the length is increased by 50%. To meet the requirements of their rapidly expanding skeletal mass, growing infants require a bioavailable source of calcium. For formula-fed infants, availability of calcium depends on the composition of the formula [Ostrom K M. et al. (2002) J. Am. Coll. Nutr.; 21(6):564-569].
The digestion of triglycerides involves lipolysis at the sn-1 and 3 positions and formation of free fatty acids and 2-monoglycerides. When palmitic acid is located at the sn-1,3 positions, as is the case in most infant formulas, it is released as free fatty acid which tends to form insoluble calcium soaps. In contrast, palmitic acid as 2-monoglyceride, as in human milk, is unavailable to form calcium soaps [Small D M. (1991) Annu. Rev. Nutr.; 11:413-434].
Several studies have shown a correlation between formulas containing high levels of palmitic acid situated at the sn-1,3 positions of the triglyceride and reduction in calcium absorption [Nelson S E. et al. (1998) J. Amer. Coll. Nutr.; 17:327-332; Lucas A. et al. (1997) Arch. Dis. Child.; 77:F178-F187; Carnielli V P. et al. (1996) J. Pediatr. Gastroenterol. Nutr. 23:553-560; Ostrom (2002) id ibid.; Hanna (1970) id ibid.]. In addition, it was shown that dietary triglycerides containing palmitic acid predominantly at the sn-2 position, as in human milk, have significant beneficial effects on the intestinal absorption of fat and calcium in healthy term infants as well as in preterm infants [Carnielli (1996) id ibid.; Carnielli (1995) id ibid.; Lucas (1997) id ibid.]. Infants fed a formula containing high levels of palmitic acid at the sn-1,3 positions showed greater fecal excursion of calcium and, hence, lower percentage absorption of calcium compared to infants fed a formula containing low levels of palmitic acid [Nelson S E. et al. (1996) Am. J. Clin. Nutr.; 64:291-296.]. Fecal excretion of calcium was closely related to the fecal excretion of fat. This study also showed that urinary phosphorus excretion increased and phosphorus retention decreased when infants were fed the formula containing high levels of palmitic acid at the sn-1,3 positions. These findings presumably reflect lower availability of calcium for deposition in bones.
Another important issue which is associated with formula feeding is constipation in both term and preterm infants which, in the latter, can lead to life threatening complications. By contrast, constipation is rare in breast fed term infants. A study comparing breast fed and formula fed infant stool hardness and composition showed that calcium fatty acid soaps are positively correlated to stool hardness. Stools from formula-fed infants were significantly harder than those of the breast-fed infants suggesting different handling of saturated fatty acids [Quinlan P T. et al. (1995) J. Pediatr. Gastr. and Nutr.; 20:81-90].
In an attempt to overcome the decreased calcium absorption and hard stool phenomena, infant formula manufacturers tend to deviate from the fatty acid profile by replacing palmitic acid with lauric acid and, in some cases, by increasing the polyunsaturated fatty acid content. Studies have shown that fatty acid composition of the diet influences the fatty acid composition of developing infant tissue [Widdowson E. M. (1975) Br. Med. J.; 1:633-5; Carlson S E. et al. (1986) Am. J. Clin. Nutr.; 44:798-804; Innis S M. et al. (1990) Am. J. Clin. Nutr.; 5:994-1000; Koletzko B. et al. (1989) Eur. J. Pediatr.; 148:669-75] and thus the lipoprotein and lipid metabolism differ between breast-fed and formula-fed infants [Putnam J. C. et al. (1982) Am. J. Clin. Nutr.; 36:106-114; Innis S M. et al. (1992) Am. Coll. Nutr.; 11:63S-8S; Van Biervliet J P. et al. (1981) Acta. Paediatr. Scand.; 70:851-6].
Innis and colleagues [Innis (1993) id ibid.], when comparing three formulas containing similar amounts of saturated fatty acids—C8-C14, C16 from palm oil (predominantly in the sn-1,3 positions), or C16 from synthesized triglyceride (predominantly in the sn-2 position)—showed that the chain length of saturated fatty acids in infant formula influences the metabolism of the dietary oleic, linoleic and alpha-linolenic acids. This study also showed that the sn-2 configuration of C16 in human milk triglycerides seems to have unique properties that extend beyond absorption. These include effects on HDL and cholesterol concentrations, and the cholesterol ester fatty acid composition.
The impact of soap formation on calcium absorption can be significant. Many infant formulas contain sufficient saturated fatty acids to form soaps with virtually all the calcium available.
U.S. Pat. No. 4,876,107 (corresponding to EP 0 209 327) describes a substitute milk fat composition which is suitable as replacement fat in infant formulations. In this fat composition the total palmitic acid residues present is as high as 45%, with at least half of the fatty acid residues at the 2-position of the glycerol backbone being palmitic. The product has about 27% palmitic acid residues at the 1- and 3-positions, and the other substituents at the 1- and 3-positions are mainly unsaturated C16 and C18 fatty acid moieties. The fat composition is prepared by a specific process, in the presence of hexane. Rather high levels of the fat compositions are required for the preparation of infant formulations.
EP 0 495 456 also discloses substitute milk fat compositions. These compositions have a saturated fatty acid content at the sn-2 position of at least 40%, most of which palmitic acid residues, and contain 0.2-7% linolenic acid moieties, 70% of which are bonded at the 1- and 3-positions of the glycerol moieties, the remaining acid moieties at the 1- and 3-positions, other than unsaturated fatty acids, are saturated C4-C12 fatty acids.
U.S. Pat. No. 5,658,768 discloses a multiple-step process for preparing triglyceride compositions in which more than 40% of the saturated fatty acid moieties are at the 2-position. Many of the steps involve enzymatic modifications.
Furthermore, lipids in the form of fatty acids hydrolyzed from triglycerides interact with minerals, either obtained from the diet or present in the body, especially calcium ions. This interaction can lead, in some cases, to the complexation for example of fatty acids and calcium ions to form insoluble complexes, which cannot be utilized by the human body and are secreted, resulting in their loss. This is actually a loss of important nutrients, since calcium is essential for skeleton building and other bodily functions, while fatty acids are an important source of energy and precursors of other lipids and nutrients.
Thus, infants and young children until the age of 3 are advised to base their nutrition on human breast milk or its replacements in the form of infant formulas, since these include in their ingredients a fat portion which mimics to some extent the fat composition of human breast milk. However, many infants and young children do not have access to such fat, either because they do not breast feed or consume infant formulas, or they consume infant formulas without human milk fat replacements, or even, above a certain age, because they supplement their nutrition with other foods, besides breast milk or infant formula. Moreover, many food products allegedly designed for the consumption of infants and young children, such as cereals, dairy products, and biscuits, are based on vegetable oils which have nothing in common with breast milk fat.
In all these scenarios, infants and young children consume fats and oils which upon their digestion create insoluble complexes with essential calcium which in turn are secreted, leading to the loss of both calcium and energy supplying lipids. This is very detrimental, since calcium is an essential nutrient during child development, in particular for skeletogenesis, i.e., bone formation.
For adults, dietary supplementation of all minerals and particularly calcium is carried out using commercial products in which the mineral can appear in different salt forms, for example calcium is in the form of calcium carbonate, calcium alginate, calcium picolinate, calcium from corals, and many other forms. In many cases, this supplemented calcium is not absorbed by the body and is secreted, or it causes digestive problems, such as constipation.
Therefore, although the dietary supplementation of minerals is needed for infants and young children, as well as adults, especially women over the age of 45, in order to treat or prevent disorders or conditions caused by mineral depletion, it is not fulfilled in a satisfactory manner.
Thus, it is an object of the present invention to provide a dietary ingredient comprising edible lipid(s), wherein said lipid has the property of enhancing the absorption and intake of minerals. Other uses and objects of the invention will become clear as the description proceeds.